Background

Early initiation of lipid-lowering therapy combined with lifestyle modifications is very effective for familial hypercholesterolemia (FH) patients in preventing cardiovascular disease (CVD) [1-3]. In additions to statins and ezetimibe, PCSK9 inhibitors can now be used for high-risk patients who do not reach their LDL-c target despite maximum therapy. PCSK9 inhibitors evolocumab and alirocumab both result in an LDL-c reduction up to 60% and are well-tolerated in general [4-7].

This study was performed to evaluate the efficacy and side effects of PCSK9 inhibitors in FH patients, in real world setting rather than in clinical trials and based on initial clinical experiences. 52 Patients received evolocumab 140 mg subcutaneously every two weeks (heFH) or 420 mg subcutaneously every two weeks (hoFH), and 31 patients received alirocumab 75 mg or 150 mg subcutaneously every two weeks (heFH).

Main results

5% of patients was homozygous for FH and 60% had a history of CVD. Other cardiovascular risk factors were frequent (66% overweight, 40% hypertension, 15% diabetes mellitus), but only 5% smokers. 71% used statins combined with ezetimibe and 49% of statin users received high-intensity statins. At baseline, mean LDL-c was 6.9±2.3 mmol/L.

PCSK9 inhibition resulted in a mean LDL-c decrease of 55%±21%; in heFH 56%±20% and in hoFH 38%±32%. No difference in LDL-c reduction between evolocumab and alirocumab. Genetic heFH patients had less LDL-c decreased than those with clinical heFH (53% vs. 67%, P<0.001).

Three hoFH patients had at least 1 defective LDLR mutation and showed 50% LDL-c reduction, whereas 1 hoFH patient with a mutation of unknown effect on LDLR activity did not have any LDL-c reduction.

Statin-intolerant patients had less LDL-c decreased compared to patients who used PCSK9 inhibitors on top of statin therapy (47% vs. 58%, P=0.03).

Treatment goal of ≤2.5 mmol/L was achieved in 55% of patients without CVD and goal of ≤1.8 mmol/L was achieved in 60% of patients who were known with CVD. In total, 58% were on-target after PCSK9 therapy.

Fourteen patients (17%) reached very low LDL-c levels (<1.0 mmol/L). On the other hand, 11% were hypo- or non-responders.

None of the patients had problems using the auto-injector. All patients were adherent and 2 patients reported technical problems.

After 6 weeks on average, 39% of patients reported one or more side effects. Most were flu-like symptoms in the first days after administration, and abdominal symptoms. 10% reported neurological symptoms.

Statin-intolerant patients had significant less side effects (21 vs 46%, P=0.05) compared to patients who still used statins.

13% had one or more injection site-reaction and 8% discontinued treatment.

Conclusion

PCSK9 inhibitors in real-world setting showed similar LDL-c reductions as those observed in randomized clinical trials. However, side effects, especially flu-like symptoms, as well as injection site-reactions were reported more often compared to clinical trials. These findings emphasize the need to establish clinical registries to monitor the long-term efficacy and side effects of PCSK9 inhibitors outside randomized clinical trials.